Presentation highlights preclinical profile for HST-1021, a highly differentiated potent, selective, and potential first-in-class MALT1 scaffolding inhibitor

BOSTON, MA, USA I June 20, 2024 I HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of oral, small molecule allosteric therapies targeting regulatory sites on proteins referred to as “natural hotspots,” today announced the presentation of preclinical data from the Company’s highly differentiated mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) program at the 4th American Association for Cancer Research (AACR) International Meeting: Advances in Malignant Lymphoma.

MALT1 is a component of the CARD11-BCL10-MALT1 (CBM) protein complex, which serves as a key regulator of NF-kB signaling in cells, including B and T cells. MALT1 is implicated in a range of hematological malignancies, including Non-Hodgkin’s lymphoma, as well as other lymphomas and selected solid tumors. Leveraging the Company’s proprietary Smart AllosteryTM platform, HotSpot has developed a potential first-in-class small molecule designed to selectively inhibit the scaffolding function of MALT1, a dominant driver of the NF-kB pathway, while sparing MALT1’s protease function.

“Given the NF-kB pathway’s role as an oncogenic driver in a range of hematological and solid tumors, the scaffolding function of MALT1, a key activator of the pathway, represents an attractive therapeutic target,” said Geraldine Harriman, Co-Founder and Chief Scientific Officer of HotSpot. “At HotSpot, we’ve utilized our Smart AllosteryTM platform to develop HST-1021, a potentially first-in-class MALT1 scaffolding inhibitor. These preclinical data support the highly differentiated profile of HST-1021, demonstrating its broad and potent inhibitory activity with no observed adverse effects on T cells.”

The presentation describes preclinical data for HST-1021, HotSpot’s MALT1 scaffolding inhibitor development candidate:

  • HST-1021 demonstrated potent inhibition of NF-kB and AP1 activity in vitro, two key markers of MALT1 scaffolding activity.
  • In contrast to MALT1 protease inhibitors, HST-1021 had no observed effect on MALT1 protease activity or T-cell function, and HST-1021 did not deplete Treg cells in vivo. HotSpot believes this supports the potential for mitigation of the risk of autoimmune disease resulting from chronic MALT1 protease function inhibition and could allow for broad combination use.
  • HST-1021 demonstrated more significant and broader anti-tumor activity as compared to a MALT1 protease inhibitor.

About HotSpot Therapeutics, Inc.
HotSpot Therapeutics, Inc. is pioneering a new class of allosteric drugs that target certain naturally occurring pockets on proteins called “natural hotspots.” These pockets are decisive in controlling a protein’s cellular function and have significant potential for new drug discovery by enabling the systematic design of potent and selective small molecules with novel pharmacology. The Company’s proprietary Smart Allostery™ platform combines computational approaches and AI-driven data mining of large and diverse data sets to uncover hotspots with tailored pharmacology toolkits and bespoke chemistry to drive the rapid discovery of novel hotspot-targeted small molecules. Leveraging this approach, HotSpot is building a broad pipeline of novel allosteric therapies for the treatment of cancer and autoimmune diseases. To learn more, visit

SOURCE: HotSpot Therapeutics